Na+-K+-ATPASE is a plasma membrane-associated enzyme which is encoded by a multigene family. Activity of the Na+-K+-ATPase provides gradients of Na+ and K+ that are essential for maintaining cellular homeostasis. (Levenson, Rev. Physiol. Biochem. Pharmacol. 123:1-45, 1994). The ion gradients established by the Na+-K+-ATPase play a central role in regulating osmotic balance, cell volume, and maintaining the resting membrane potential. Na+-coupled transport of nutrients, establishment of the ionic composition of cerebrospinal fluid and aqueous humor, electrical activity of muscle and nerve, and receptor-mediated endocytosis are all processes which depend on the activity of the enzyme.
Compounds have been identified that inhibit Na+-K+-ATPase, and at least some of these compounds, plant-derived cardiac glycosides like ouabain and digoxin, have found therapeutic utility, such as treatment of congestive heart failure. However, ouabain can also have deleterious side effects that have not been associated with the use of an endogenous compound, hypothalamic inhibitory factor (HIF), which also has been found to have an inhibitory effect on Na+-K+-ATPase.
Sensitivity of the Na+-K+-ATPase to ouabain and HIF lies within the a subunit of the enzyme. To date, all α2 and α3 isoforms and α1 isoforms from most mammals and other organisms tested are sensitive to ouabain, i.e., can be inhibited at relatively low ouabain concentrations. However, certain α1 isoforms are resistant to ouabain.
A need exists to identify other inhibitors of Na+-K+-ATPase which, like HIF, will have fewer potential side-effects than ouabain, and related cardiac glycosides obtained from plants.